Pure Appl. Chem., Vol. 83, No. 3, pp. 607–612, 2011.

doi:10.1351/PAC-CON-10-09-15
© 2011 IUPAC, Publication date (Web): 31 January 2011

Oxidative decarboxylation of ␣-amino acids to

nitriles using o-iodoxybenzoic acid in aqueous
ammonia*
Eknath V. Bellale, Sameerana N. Huddar, Ulhas S. Mahajan, and
Krishnacharya G. Akamanchi‡
Department of Pharmaceutical Sciences & Technology, Institute of Chemical
Technology, Matunga, Mumbai 400 019, India

Abstract: Formation of the nitrile was the outcome of the investigation of biochemically sig-
nificant oxidative decarboxylation of amino acids using o-iodoxybenzoic acid (IBX) in aque-
ous ammonia system.

Keywords: amino acids; decarboxylation; o-iodoxybenzoic acid; nitrile; oxidation.

INTRODUCTION
Oxidative decarboxylation of α-amino acids is an important metabolic transformation in a variety of
organisms. It finds applications in biochemistry and peptide cleavages [1], such as reaction of coenzyme
pyrroloquinolinequinone (PQQ) and amino acids [2], decarboxylation of certain N,N-dialkylamino
acids toward selective generation of synthetically useful enamine functions in specific positions of
given molecules [3], and decarboxylative functionalization of α-amino acids for construction of useful
motifs [4]. It is also a reaction of significance in understanding the action of chlorine components as
sanitizers in food industry [5]. Because of its importance, this transformation in the field of synthetic
organic chemistry and biological chemistry has attracted the attention of chemists.
Many reagents have been investigated toward oxidative decarboxylation of α-amino acids, which
give nitrile or a mixture of nitrile and aldehyde as the products depending on reaction conditions and
reagents employed [6,7]. Oxidation with 1-chlorobenzotriazole (CBT) [6a] and trichloroisocyanuric
acid [6b,c] nitriles were formed in the range of 90–99 %, whereas lower yields (53–83 %) were
observed with copper(II) bromide-lithium tert-butoxide [6d] reagent. However, oxidation with other
oxidizing agents such as sodium hypobromite [7a], N-bromosuccinimide [7b,c], t-BuOCl [7d], chlo-
ramine-T [7e,f], enzyme bromoperoxidase [7g], and electrolytic method using silver electrode [7h], a
mixture of aldehydes and nitriles was formed in varying ratios depending on reaction conditions
employed.
Hypervalent iodine(III) reagents have been investigated for the oxidative decarboxylation.
Reaction with [1,1-bis(trifluoroacetoxy)iodo]benzene/pyridine [8a] reagent, a mixture of aldehyde and
nitrile was formed in different ratios depending on the reaction conditions whereas with the iodoso-
benzene diacetate/iodine [8b] system, decarboxylative β-iodination occurred. The oxidative decarboxy-
lation has been studied using (PhIO)n as oxidant but only with cyclic amino acids as substrates to give

*Paper based on a presentation made at the 18th International Conference on Organic Synthesis (ICOS-18), Bergen, Norway, 1–6
August 2010. Other presentations are published in this issue, pp. 411–731.
‡Corresponding author: Tel.: +912233611111; Fax: +912233611020; E-mail: [email protected]

607
608 E. V. BELLALE et al.

lactams as products [8c]. Similar oxidations attempted on amino acids tyrosine and tryptophan with
iodosobenzene diacetate resulted in formation of 4-(methoxymethyl)phenol and 3-(methoxymethyl)-
1H-indole, respectively [8d,e].
Hypervalent iodine(V) reagents, especially o-iodoxybenzoic acid (IBX) and Dess–Martin perio-
dinane (DMP), are of current interest, and using them in a variety of oxidative transformations is being
reported as evidenced by recent reviews [9]. Mild, selective, and wide reactivity spectrum of IBX is
responsible for its popularity as oxidant in the synthesis of complex natural products and, in general,
synthetic organic chemistry [10]. Our research group is actively investigating oxidative transformations
using IBX and DMP [11]. IBX being acid is readily soluble in aqueous ammonia and is very stable.
Recently, we have reported a facile transformation of aldehyde to nitrile in almost quantitative yield
using IBX in aqueous ammonia exploiting fast oxidation of aldimines by IBX [11c,12]. Considering the
importance of oxidation of α-amino acids and current interest in hypervalent iodine(V) reagents and
facile conversion of aldimines to nitrile by IBX in aqueous ammonia systems, we investigated hyper-
valent iodine(V) reagents, particularly IBX in aqueous ammonia, for the oxidative decarboxylation. The
results are presented here.

RESULT AND DISCUSSION

Preliminary experiments were carried out using α-phenylglycine 1a as model substrate, and results are
summarized in Table 1. α-Phenylglycine 1a was treated with IBX in aqueous ammonia at rt for 12 h
but reaction did not occur. The experiment was repeated at elevated temperature, and at 75 °C the reac-
tion occurred rapidly, yielding 95 % of benzonitrile 2a in just 30 min (Table 1, entries 1 and 2). To
ascertain the role of ammonia, an experiment was conducted with only water as solvent and as expected
practically there was no reaction even at 75 °C and this was attributed to insolubility of IBX in water,
because when a cosolvent such as dimethylsulfoxide (DMSO) was added, the reaction occurred giving
a mixture of benzonitrile and benzaldehyde (Table 1, entries 3–5).

Table 1 Optimization of reagent and reaction conditions.a

Entry Reagent/solvent Temperature Time (min/h) Yield (%)b

(°C) 2a
1 IBX/aqueous ammonia rt 12 h NRc
2 IBX/aqueous ammonia 75 30 min 95
3 IBX/water rt 12 h NRc
4 IBX/water 75 7h NRc
5 IBX/DMSO:water rt 1h 80d
6 DMP/aqueous ammonia 75 45 min 89
aReaction performed on 5 mmol of 1a.
bYieldsobtained after column chromatography.
cNR = No reaction.
d5 % of benzaldehyde was isolated.

Therefore, it can be concluded that the aqueous ammonia is playing the dual role of a solvent and
as well as favoring equilibrium toward aldimine intermediate, leading to nitrile as the sole product

© 2011, IUPAC Pure Appl. Chem., Vol. 83, No. 3, pp. 607–612, 2011
 Oxidation of amino acids 609

Table 2 Oxidative decarboxylation of α-amino acids to corresponding nitriles.a

aReactions were carried out on 5 mmol scale in aqueous ammonia at 75 °C with IBX (2.5 equiv).
bAll products obtained were known compounds and were characterized by IR, 1H NMR and compared with standard.
cYields by column chromatography.
dIsolated as ethyl ester.

© 2011, IUPAC Pure Appl. Chem., Vol. 83, No. 3, pp. 607–612, 2011
610 E. V. BELLALE et al.

instead of a mixture of aldehyde and nitrile [12]. DMP was also found to be viable for the reaction, and
results were similar (Table 1, entry 6).
To study generality and chemoselectivity, a variety of α-amino acids were subjected to the reac-
tion conditions, and the results are summarized in Table 2. The results indicate that reaction was com-
paratively fast with arylglycines (Table 2, entries 1–3) as compared to alkylglycines (Table 2, entries
6–10). In the case of arylalkyl glycines, the reaction was equally facile and a noteworthy feature is that
the benzylic position remained unaffected (Table 2, entries 4 and 5). Both glutamic acid 1i and methio-
nine 1j underwent smooth transformation to give corresponding nitriles with intact carboxylic acid and
thioether moieties, respectively (Table 2, entries 9 and 10), indicating chemoselectivity.
Mechanism postulated for the transformation is depicted in Scheme 1 where IBX–amino acid
adduct C formed in the first step undergoes decarboxylation to form aldimine intermediate D and which
on subsequent oxidation gives nitrile [12]. Because of the high concentration of ammonia, equilibrium
is favored toward aldimine leading to formation of nitrile as the sole product instead of a mixture of
aldehyde and nitrile as observed in the case of hypervalent iodine(III) reagent system, [1,1-bis(trifluoro-
acetoxy)iodo]benzene/pyridine and others.

Scheme 1 Postulated mechanism for oxidative decarboxylation of amino acids to nitriles.

CONCLUSION
In conclusion, it can be said that IBX in aqueous ammonia brings about chemoselective and rapid
oxidative decarboxylation of α-amino acids to produce nitriles as sole product in very high yields.
Aqueous ammonia plays a dual role as a solvent for IBX and favoring equilibrium toward aldimine so
that formation of aldehyde is avoided.

© 2011, IUPAC Pure Appl. Chem., Vol. 83, No. 3, pp. 607–612, 2011
 Oxidation of amino acids 611

SUPPLEMENTARY INFORMATION
Experimental procedure and characterization of compounds can be found in the supplementary infor-
mation, which is available online (doi:10.1351/PAC-CON-10-09-15).

ACKNOWLEDGMENTS
E.V.B. thanks the World Bank for their financial assistance under TEQIP. S.N.H. thanks the Narottam
Shekhsaria Foundation, Mumbai, for financial assistance. The authors also wish to thank the University
Grants Commission (UGC) of India and the All India Council for Technical Education (AICTE) for
financial support.

REFERENCES
1. D. Macmillan. Angew. Chem., Int. Ed. 45, 7668 (2006).
2. S. Itoh, M. Mure, A. Suzuki, H. Murao, Y. Ohshiro. J. Chem. Soc., Perkin Trans. 2 1245 (1992).
3. E. E. van Tamelen, V. B. Haarsad, R. L. Orvis. Tetrahedron 24, 687 (1967).
4. (a) R. Fan, W. Li, B. Wang. Org. Biomol. Chem. 6, 4615 (2008); (b) H.-P. Bi, L. Zhao, Y.-M.
Liang, C.-J. Li. Angew. Chem., Int. Ed. 48, 792 (2009).
5. N. G. Marriott, R. B. Garvani. Principles of Food Sanitation, p. 170, Springerlink + Business
Media, New York (2006).
6. (a) R. C. Hiremath, S. M. Mayanna, N. Venkatasubramanian. J. Chem. Soc., Perkin Trans. 2 1569
(1987); (b) L. De Luca, G. Giacomelli. Synlett 2180 (2004); (c) G. A. Hiegel, J. C. Lewis, J. W.
Bae. Synth. Commun. 34, 3449 (2004); (d) T. Takeda, S. Yamauchi, T. Fujiwara. Synthesis 600
(1996).
7. (a) A. H. Friedman, S. Morgulis. J. Am. Chem. Soc. 58, 909 (1936); (b) G. W. Stevenson, J. M.
Luck. J. Biol. Chem. 236, 715 (1961); (c) S. P. Musharan, J. N. Tiwari, A. K. Bose, K. Singh. Ind.
J. Chem. 16A, 35 (1980); (d) B. T. Gowda, B. S. Moodithaya, B. H. Arun Kumar. Oxidation
Commun. 24, 74 (2001); (e) H. D. Dakin. Biochem. J. 10, 319 (1916); (f) J. Sharma, L. Pandey,
S. P. Musharan. Ind. J. Chem. 19A, 475 (1980); (g) M. Nieder, L. Hager. Arch. Biochem. Biophys.
240, 121 (1985); (h) N. A. Hampson, J. B. Lee, K. I. MacDonald, M. J. Shaw. J. Chem. Soc. (B)
1766 (1970).
8. (a) A. Boto, R. Hernandez, Y. de Leon, E. Suarez. J. Org. Chem. 66, 7796 (2001); (b) G. M.
Loudon, A. S. Radhakrishna, M. R. Almond, J. K. Blodgett, R. H. Boutin. J. Org. Chem. 49, 4272
(1984); (c) M. Ochiai, M. Inenaga, Y. Nagao. Tetrahedron Lett. 29, 6917 (1988); (d) R. M.
Moriarty, M. Sultana, Y.-Y. Ku. J. Chem. Soc., Chem. Commun. 974 (1985) (e) R. M. Moriarty,
M. Sultana. J. Am. Chem. Soc. 107, 4559 (1985).
9. (a) V. V. Zhdankin, P. J. Stang. Chem. Rev. 102, 2523 (2002); (b) V. V. Zhdankin. Curr. Org. Synth.
2, 121 (2005); (c) P. J. Stang, V. V. Zhdankin. Chem. Rev. 96, 1123 (1996); (d) V. V. Zhdankin,
P. J. Stang. Chem. Rev. 108, 5299 (2008); (e) V. Satam, A. Harad, R. Rajule, H. Pati. Tetrahedron
66, 7659 (2010).
10. (a) F. F. Paintner, L. Allmendinger, G. Bauschke. Synthesis 2113 (2001); (b) S. Kirsch, T. Bach.
Angew. Chem., Int. Ed. 42, 4685 (2003); (c) J. D. More, N. S. Finney. Synlett 1307 (2003); (d)
J. M. VanderRoest, P. A. Grieco. J. Org. Chem. 61, 5316 (1996); (e) F. Lach, C. J. Moody.
Tetrahedron Lett. 41, 6893 (2000); (f) J. M. Bueno, J. M. Coteron, J. L. Chiara, A. Fernandez-
Mayoralas, J. M. Fiandor, N. Valle. Tetrahedron Lett. 41, 4379 (2000); (g) D. Weigelt,
R. Krahmer, K. Bruschke, L. Hennig, M. Findeisen, D. Muller, P. Welzel. Tetrahedron 55, 687
(1999); (h) M. A. Gonzalez. Tetrahedron 64, 445 (2008).

© 2011, IUPAC Pure Appl. Chem., Vol. 83, No. 3, pp. 607–612, 2011
612 E. V. BELLALE et al.

11. (a) V. G. Shukla, P. D. Salgaonker, K. G. Akamanchi. J. Org. Chem. 68, 5422 (2003); (b) D. S.
Bhalerao, U. S. Mahajan, K. H. Chaudhari, K. G. Akamanchi. J. Org. Chem. 72, 662 (2007); (c)
E. V. Bellale, D. S. Bhalerao, K. G. Akamanchi. J. Org. Chem. 73, 9473 (2008); (d) U. S.
Mahajan, K. G. Akamanchi. Synth. Commun. 39, 2674 (2009); (e) P. D. Salgaonkar, V. G. Shukla,
K. G. Akamanchi. Synth. Commun. 35, 2805 (2005).
12. N. D. Arote, D. S. Bhalerao, K. G. Akamanchi. Tetrahedron Lett. 48, 3651 (2007).

© 2011, IUPAC Pure Appl. Chem., Vol. 83, No. 3, pp. 607–612, 2011